Throughout this specification, including the claims which follow, unless the context requires otherwise, the word “comprise,” and variations such as “comprises” and “comprising,” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a pharmaceutical carrier” includes mixtures of two or more such carriers, and the like.
Ranges are often expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent “about,” it will be understood that the particular value forms another embodiments.
Phenolic xenobiotics can be modified by cellular systems in a number of ways, e.g., oxidation, glucoronidation, sulphation, methylation, acetylation, etc., and the instability of certain phenolic protein tyrosine kinase (PTK) inhibitors has been documented. For example, the antitumor PTK inhibitor erbstatin, shown below, is known to have a short half-life (<30 min) in fetal calf serum (see, e.g., Umezawa et al., 1991), and the lack of correlation between the activity of tyrphostins, shown below, against isolated enzymes and their effects in vitro and in vivo, is noteworthy (see, e.g., Rambas et al., 1994). Di- and tri-phenolic tyrphostins decompose in solution to more active PTK inhibitors (see, e.g., Faaland et al., 1991), whereas tyrphostins devoid of hydroxy groups have a rapid onset of cellular activity (see, e.g., Reddy et al., 1992), implicating metabolic oxidation to a quinone (or other) moiety as a possible bioactivating step.

The present invention pertains to compounds which may be considered to be the oxidation products of bioactive phenols, and analogues thereof. Such oxidation products include, e.g., optionally substituted 4-aryl-cyclohexa-2,5-dienones (4-aryl quinols), 4-aryl-4-substituted-cyclohexa-2-enones, 4-aryl-4-substituted-cyclohexanones, sulfonamide analogs, and the like.
Callinan et al., 1990, describe the synthesis of certain phenyl substituted quinol ethers, shown below, where R is, for example, —H, -Me, —OMe, —CH═CH2.

Weesely et al., 1952, describe the synthesis of certain substituted quinols, shown below, where R is, for example, —H or —Ac; R1 is -Me or -Ph; and R2 and R3 are —H or -Me.

Capparelli et al., 1987, describe the synthesis of certain substituted quinols, shown below, where, for example, R is —H or -Me; R1 is -Et, -iPr, -tBu, —CH2Ph, -Ph, methyl or methoxy subsituted -Ph, or thiophen-2-yl; R2 is —H or -Me; and, R3 is —H or —OMe.

Wells et al., 2000, describe several benzothiazole substituted quinol derivatives, shown below, where R1 is —Ac, -Me, -Et, -nPr, or —CH2C═CH (denoted herein as Q5, Q15, Q16, Q17, Q18, Q19, and Q20, respectively), and R2 is -Me or -Et. These compounds were reported to have activity against certain colon (HCT-116 and HT29) and breast (MCF-7 and MDA468) cancer cell lines in vitro. Note that there is no mention of possible application to Mycobacteria infections, or as thioredoxin/thioredoxin reductase inhibitors.

Two compounds that contain a hydroxycyclohexadienone structure and which apparently have antitumor activity have been reported: a hydroxylated flavone-substituted quinol (i.e., a chromone substituted quinol) (see, e.g., Wada et al., 1987) and an oxidized estrone (see, e.g., Milic et al., 1999).

Several related antitumor epoxyquinols, such as Manumycin A (see, e.g., Alcaraz et al., 1998) and LL-C 10037α (see, e.g., Wipf et al., 1994) are known.
